Novel D-ring analogues of podophyllotoxin as potent anti-cancer agents

Insulin is one of the hormonal regulators of leptin synthesis and participates in adipose tissue maintenance. The present study was undertaken to clarify the association of endogenous insulin secretion and mode of therapy with body fat and serum leptin levels in diabetic subjects. We measured the fasting serum C-peptide level, as an estimate of endogenous insulin secretion, and the serum leptin level in 176 Japanese diabetic subjects (79 men and 97 women; age, 55.9+/-14.3 years; body mass index [BMI], 23.8+/-4.1 kg/m2 [mean+/-SD]). Thirty-one subjects were treated with diet therapy alone, 66 with sulfonylurea (SU), and 79 with insulin (including 29 with type I diabetes mellitus). Body fat was analyzed by the impedance method. Serum leptin levels significantly correlated with the BMI and body fat and were higher in women, mainly because of their greater body fat. Serum C-peptide concentrations positively correlated with body fat and serum leptin in subjects treated with diet and SU. In insulin-treated type II diabetic subjects, both serum C-peptide and the daily insulin dose were weakly associated with body fat and serum leptin. In those subjects, despite a lower percent body fat and body fat mass, serum leptin concentrations (10.3+/-8.4 ng/mL) were comparable to the levels in subjects treated with diet (8.8+/-8.5 ng/mL). When compared within the same BMI and body fat groups (BMI 20 to 25 and > 25 kg/m2) including the control subjects matched for age and sex, serum leptin levels were higher in insulin-treated type II diabetic subjects versus the control subjects and diabetic patients treated with diet or SU. Stepwise regression analysis for all of the diabetic subjects showed that both the serum C-peptide level and exogenous insulin administration, as well as the BMI, gender, and age, were determinants of the serum leptin level. In conclusion, endogenous insulin secretion is closely associated with body fat and serum leptin in diabetic subjects treated with diet therapy and SU. In Japanese insulin-treated type II diabetic subjects, both endogenous and exogenous insulin are associated with body fat and serum leptin, which is maintained at levels comparable to or somewhat higher than the levels in control subjects and diabetic patients treated without insulin.     

Protection of both auditory hair cells and auditory neurons from cisplatin induced damage

Knowledge about body composition is important in metabolic and nutritional studies. In this cross-sectional study the body composition of 403 healthy white Dutch children and adolescents was evaluated by using dual-energy X-ray absorptiometry (DXA). Possible determinants of body composition were analyzed. In 85 subjects the results of bioelectrical impedance analysis (BIA) were compared with DXA. Fat mass, lean tissue mass, and bone mineral content were greater in older boys and girls. Percentage body fat was greater in older girls but not in boys and it was higher in girls than in boys at all ages. From the age of 14 y boys had higher lean tissue mass and bone mineral content than girls. Tanner stage had a significant relation with body composition in both sexes. Percentage body fat was lower in boys in stage 4 than in stage 3 and was higher in consecutive Tanner stages in girls. After adjustment for age, Tanner stage was significantly positively related to lean tissue mass and bone mineral content in boys and girls and to percentage body fat and fat mass in girls. The profession of the parents and the education of the father had a significant negative correlation with percentage body fat and fat mass in girls (P < 0.01). Physical activity was related to lean tissue mass (P = 0.001) but not to fat mass in boys after adjustment for age. A high correlation and a small difference was found between lean body mass by BIA and lean tissue mass by DXA. Body composition in healthy Dutch children and adolescents is related to age, sex, Tanner stage, socioeconomic status, and physical activity.     

Thalamic NMDA transmission in a genetic model of absence epilepsy in rats

OBJECTIVES: Whether menopause per se influences fat distribution independently of the effect of aging remains controversial. The lack of consistency in the menopause related changes in body fat distribution may be the result of differences in the methods for measuring fat distribution or in the characteristics of the women studied. The aim of this cross sectional study in obese women was to compare total body composition and regional fat and lean distribution, in premenopausal, perimenopausal and postmenopausal women. METHODS: Body composition was assessed by dual energy X-ray absorptiometry (DEXA) in premenopausal (n = 26), perimenopausal (n = 24) and postmenopausal (n = 73) obese women with no intercurrent diseases. RESULTS: It was shown that postmenopausal obese (n = 73) women had a higher proportion of total fat mass in the trunk and a lower proportion of total fat and lean mass in the femoral and leg regions than premenopausal women after adjustment for age and total fat mass. In the same analysis, perimenopausal women had a lower proportion of total fat in the leg and femoral regions and of total lean in the femoral region than premenopausal women; they had a regional body composition similar to that of postmenopausal women. CONCLUSION: The present data indicate that in obese women, post menopause and perimenopause are associated with differences in fat and lean distribution, independently of age and total fat.     

Body composition in normal subjects: relation to lipid and glucose variables

OBJECTIVE: To describe sex- and age-dependent values of total and regional body composition as determined by dual-energy X-ray absorptiometry (DXA) in normal subjects, and furthermore to relate body composition measurements to blood lipids, glucose and insulin concentrations. DESIGN: A cross-sectional study. SUBJECTS: 173 (84 male and 89 female) healthy subjects, BMI < 30 kg/m2. MEASUREMENTS: Body composition parameters including data on total bone mineral content (TBMC), total bone mineral density (TBMD), lean body soft tissue mass (LTM), total and regional fat mass (FM) were estimated in all subjects. In 87 of the subjects fasting blood glucose, S-insulin and lipid profile were measured. RESULTS: The study population was for each sex divided into five decades for which results on body composition and blood lipids are presented. Body weight increased 2 kg per age decade, representing a significant increase in both total FM and relative FM (FM%BW) with age, and in males a central accumulation of FM. LTM decreased significantly in males but not in females, whereas TBMC and TBMD remained constant in males, but decreased in females. A significant correlation between relative FM and S-cholesterol, S-triglyceride, and in males S-insulin was found. CONCLUSION: The present study gives coherent data on bone mineral content, lean body soft tissue mass total and regional fat mass for 173 healthy subjects with a BMI below 30 kg/m2. Total body fat mass increases, and lean mass decreases with age. In males a simultaneous central accumulation of fat mass is observed. The well-known relationship between central obesity and lipids is confirmed even in non-obese subjects.     

Gender-dependent alterations in serum leptin in alcoholic cirrhosis

BACKGROUND & AIMS: Leptin is a peptide that decreases food intake and increases energy expenditure. It is produced in fat cells, is stimulated by cytokines, and its levels in serum are higher in females. Because anorexia, hypermetabolism, and elevated cytokine levels are frequently observed in cirrhosis, we hypothesized that the serum leptin level would be elevated in cirrhosis. The aim of this study was to investigate the relationship of serum leptin to gender, body composition, and tumor necrosis factor (TNF). METHODS: Male (n = 18) and female (n = 10) abstinent alcoholic cirrhotic patients were studied and compared with control subjects (15 male and 8 female). Fat mass, fat-free body mass, and body cell mass were calculated by using H2[18O] and bromide dilution methodology. Serum leptin and TNF concentrations were measured by immunoassays. RESULTS: Fat mass was decreased only in male cirrhotics (P < 0.05), whereas body cell mass was decreased in both male and female cirrhotics (P < 0.01). Leptin levels were elevated in female (P < 0. 001) but not male cirrhotics compared with controls. When expressed per kilogram of fat mass, leptin was elevated in both male (P < 0. 01) and female (P < 0.01) cirrhotics. Women in both cirrhotic and control groups had higher leptin levels than men. TNF was elevated in both male and female cirrhotics and did not correlate with leptin levels. CONCLUSIONS: Cirrhotics have elevated serum leptin levels, which are related to both gender- and gender-dependent alterations in body composition.     

Serum leptin and energy expenditure in children

Leptin has been hypothesized to play an important role in energy balance by affecting both energy intake and energy expenditure. The purpose of our study was to determine the relationship between fasting serum leptin concentrations and measures of energy expenditure in prepubertal children. We measured total energy expenditure (TEE; by the doubly labeled water technique), resting energy expenditure (REE; after an overnight fast), activity energy expenditure (AEE; TEE-REE), body composition (by dual energy x-ray absorptiometry), and fasting serum leptin concentration (by RIA) in 76 children. Simple correlations showed that all measures of energy expenditure (TEE, REE, and AEE) were positively related to the serum leptin concentration (r = 0.50, P < 0.001; r = 0.45, P < 0.001; and r = 0.30, P < 0.01, respectively). However, after adjusting for body composition (fat-free mass and fat mass), gender, and ethnicity, serum leptin concentrations were not related to any measure of energy expenditure (TEE, P = 0.61; REE, P = 0.97; AEE, P = 0.65). These latter findings were further confirmed using structural equation models with leptin and energy expenditure as dependent variables, and fat-free mass and fat mass as independent variables. Results from these models showed no direct effect of leptin and no indirect effect of fat mass (through leptin) on any measure of energy expenditure, when a path between fat mass and energy expenditure was present in the model. Thus, our data do not support the hypothesis that the serum leptin concentration (independent of fat mass) is related to measures of energy expenditure in children.     

Serum leptin levels in male marathon athletes before and after the marathon run

Leptin is a hormone produced by the adipocytes to regulate food intake and energy expenditure at the hypothalamic level. It is commonly accepted that the main determinants of leptin secretion are the net amount of body fat and the mean size of adipocytes. On the contrary, important vectors of energy flux in the organism, such as food intake and energy expended on exercise, are not thought to be regulators of that secretion. To understand whether leptin is regulated by an acute energy expenditure such as strenuous exercise, 29 male athletes who had trained for marathon running were studied before and after a marathon run and compared with 22 nonobese, age-, sex-, and body mass index (BMI)-matched sedentary controls. Controls and marathon athletes showed no differences in BMI or fat-free mass. Marathon runners showed a strong reduction in total fat mass (6.2 +/- 0.4 kg; 9.1 +/- 0.5% of body fat) compared with controls (12.3 +/- 0.5 kg; 16.1 +/- 0.5% of body fat; P < 0.05). This difference in body composition was paralleled by a mean serum leptin level that in marathonians (2.9 +/- 0.2 micrograms/L) was significantly (P < 0.05) reduced compared with that in controls (5.1 +/- 0.6 micrograms/L). It is remarkable that the ratio of leptin per kg body fat, showed a very good agreement between the two groups, 0.40 +/- 0.04 microgram/L.kg for controls and 0.46 +/- 0.03 microgram/L.kg for marathonians. In the two groups, leptin was correlated with both body weight, BMI, and fat mass (P < 0.001). The marathon trajectory was the standard 42.195 km accomplished in an average time of 3 h, 17 min, 7 s, with a calculated energy expenditure of over 2800 Cal. After the marathon run, a water imbalance occurred, with a significant decrease in body weight and an increase in serum albumin. A significant (P < 0.05) reduction in leptin values was observed after the run (2.6 +/- 0.2 micrograms/L) compared with before (2.9 +/- 0.2 micrograms/L), which was more relevant considering the relative hemoconcentration. In conclusion, 1) compared with sedentary subjects, leptin levels are reduced in male marathon runners in parallel with the relevant reduction in total body fat; 2) expressed as a ratio of leptin per kg body fat, no differences were observed between marathonians and controls; and 3) after an energy expenditure of 2800 Cal in the marathon run, a reduction in leptin levels occurred. Strong changes in energy expenditure may regulate serum leptin levels in man.     

Effects of gender, body composition, and menopause on plasma concentrations of leptin

Circulating concentrations of leptin ([leptin]) vary directly with body mass index and percentage body fat, and may thus constitute an afferent limb of a system regulating body fatness. We tested the hypotheses that: 1) Plasma [leptin] vary more directly with absolute fat mass than with fractional body fatness per se: and 2). The relationship between fat mass and [leptin] is significantly affected by gender and by menopausal status. [Leptin] in the post-absorptive state was examined in 67 subjects (26 male, 20 premenopausal female, 21 postmenopausal females; 43 never-obese, 24 obese) at usual body weight. Body composition was determined by hydrodensitometry, and [leptin] was determined by a double antibody ELISA assay. In male and pre-menopausal female subjects, subcutaneous adipose tissue aspirations were performed for determination of adipocyte volume by the osmium fixation method, and a 3 hour oral glucose tolerance tests was performed. At usual body weight, ([leptin]) was better correlated with absolute fat mass than with body mass index (BMI) or percentage body fat. BMI and % body fat did not account for any of the variance in [leptin] beyond that attributable to FM, per se. The regression equations relating FM to [leptin] did not differ significantly between obese and never-obese subjects. [Leptin] and fasting serum insulin concentrations were significantly correlated in males only. [Leptin] was significantly higher in pre- and post-menopausal females compared to males, even when [leptin] was corrected for differences in body composition (pre-menopausal females > post-menopausal females > males). While plasma [leptin], corrected for FM, declines significantly in women post-menopause, this decline is not sufficient to account for the striking sexual dimorphism in the relationship of leptin to fat mass. This sexual dimorphism is apparently also due, in part, to a suppressive effect of circulating androgens on [leptin].     

Serum leptin is increased in growth hormone-deficient adults: relationship to body composition and effects of placebo-controlled growth hormone therapy for 1 year

The gene product from the ob gene, leptin, has recently been characterized in humans. The circulating level of leptin is related to body mass index (BMI) and more closely to estimates of total body fat, whereas visceral fat has been reported to be of minor importance. However, it is unknown if leptin is directly regulated by hormones that influence substrate metabolism and body composition. We studied leptin in adult growth hormone (GH)-deficient (GHD) patients substituted with GH treatment for 12 months in a parallel double-blind, placebo-controlled study. Twenty-seven GHD adults aged 44.9 +/- 1.9 years underwent anthropometric measurements for determination of regional and total body fat (BMI, waist to hip ratio [WHR], computed tomographic [CT] scan, dual-energy x-ray absorptiometry [DEXA] scan, and bioimpedance analysis [BIA]) before and after 12 months of placebo-controlled GH substitution (2 IU/m2) in a parallel design. The same measurements were performed in 42 healthy adults aged 39.1 +/- 1.7 years. The logarithm of serum leptin levels correlated positively with abdominal subcutaneous fat and total body fat (BIA and DEXA) in untreated GHD patients and healthy subjects. Fasting insulin did not correlate with leptin levels in either of the groups. After 12 months of GH administration, the body composition of GHD patients was significantly changed with respect to a marked decrease in body fat. The relations of leptin to the estimates of body fat were maintained, and leptin was furthermore related to BMI and fasting insulin. In multiple linear regression analyses, additional estimates of visceral adiposity (intraabdominal fat and maximal anterior-posterior diameter determined by CT scan) were significant determinants of leptin in the healthy subjects. The increase in fasting insulin levels during GH substitution correlated negatively with the reduction in leptin levels (r = -.823, P = .003). At baseline, leptin levels were increased in the patients compared with controls in both sexes (women, 21.8 +/- 3.3 v 11.3 +/- 1.4 ng/mL, P = .002; men, 8.1 +/- 1.2 v 4.7 +/- 0.7 ng/mL, P = .008). Leptin levels were similar in GHD patients treated for 12 months compared with healthy controls for both women and men (women, 15.9 +/- 2.3 and 11.3 +/- 1.4 ng/mL, P = .163; men, 7.1 +/- 2.8 and 4.7 +/- 0.7 ng/mL, P = .759). In healthy adults and in GHD patients, leptin levels were significantly higher in women than in men (11.3 +/- 1.4 v 4.7 +/- 0.7 ng/mL, P < .001; 21.8 +/- 3.3 v 8.1 +/- 1.2 ng/mL, P < .001). Gender remained a significant determinant of leptin levels in several models of multiple linear regression analysis also including age, estradiol levels, insulin, and estimates of body fat. We conclude that leptin is increased but not differently regulated in GHD patients compared with normal subjects, and that leptin levels are closely related to estimates of body fat. This relationship is maintained during a decrease in body fat due to GH substitution.     

Effect of sex and age on bone mass, body composition and fuel metabolism in humans

The mechanism(s) governing the gain of upper-body fat and its relationship to the decrease in bone mass with age is still unclear. Therefore, four groups of subjects matched for weight, height, and body mass index (n = 119; 60 women, 59 men), but differing in age (above and below 50 y) and sex were investigated using dual energy x-ray absorptiometry (DXA) to assess body composition (bone, lean, and fat mass as well as its distribution) and indirect calorimetry to determine resting fuel metabolism. Fat mass of trunk and arms (P < 0.01), but not legs, increased with advancing age in males, resulting in a continuous increase in the ratio of upper- to lower-body fat (r = 0.45, P < 0.001). In contrast, total fat mass remained stable in women, irrespective of menopause, but a redistribution of fat occurred with advancing age (r = 0.43, P < 0.001), resulting in a higher upper- to lower-body fat ratio (P < 0.05) in older than in younger women. Total lean soft-tissue mass of all segments of the body was greater in men than in women irrespective of age (P < 0.001), and lower in the older groups than in the younger ones irrespective of sex. In males, but not females, lean soft-tissue mass in arms and legs decreased (r = 0.57, P < 0.001), whereas the ratio of total fat to lean soft-tissue mass increased (r = 0.53, P < 0.001) with age. Bone mineral content correlated with total body fat in both groups of women and in young males (r > 0.5, P < 0.001), but not in older males. With advancing age, the proportion of lean soft-tissue mass occupied by total skeleton declined in women (n = 59, P < 0.001), but remained stable in males. Resting energy expenditure decreased with age in both sexes. Protein and carbohydrate oxidation were similar in all four groups of subjects. Total fat oxidation and fat oxidation per kilogram of lean soft-tissue mass decreased with age (r > 0.36, P < 0.01) in males, but not in females, whereas it increased with increasing fat mass in females (r > 0.32, P < 0.03), but not in males. In contrast, fat oxidation per kilogram of fat mass decreased with fat mass in males (r = 0.61, P < 0.001), but not in females. Our results suggest that aging affects body composition and fuel metabolism differently in each gender, leading to reduced fat oxidation and accumulation of upper-body fat with loss of striated muscle in men, and to an increased ratio of upper- to lower-body fat and bone loss in women, the latter depending on fat mass.     

The high-fat phenotype: is leptin involved in the adaptive response to a high fat (high energy) diet?

OBJECTIVE: To investigate physiological differences which could influence the balance between energy expenditure and energy intake, between habitual high-fat (HF) and low-fat (LF) consumers and the potential for weight gain. SUBJECTS: Ten HF and nine LF consumers, all young, lean males (% energy from fat 45.4 and 31.8, respectively). MEASUREMENTS: Habitual dietary variables (from the food frequency questionnaire, FFQ), body mass index (BMI), % body fat (% BF, measured by impedance), fasting concentrations of plasma leptin, glucose and triglycerides. RESULTS: HF and LF subjects (selected for their fat intake) did not differ significantly in BMI or % BF. HF subjects had significantly higher concentrations of plasma leptin and lower concentrations of plasma glucose than LF subjects. In all subjects, concentrations of fasting plasma leptin correlated significantly with BMI, % BF and fat mass; difference in leptin between groups remained significant when BMI and % BF were used as covariants. Leptin significantly correlated with dietary variables; particularly dietary fat (% energy and g) and inversely with dietary carbohydrate (% energy), but showed no correlation with dietary protein or total energy intake. CONCLUSION: Significant differences in concentrations of fasting plasma leptin have been observed between lean male HF and LF consumers. These findings suggest that the difference in leptin concentrations could be associated with a metabolic adaptation which could help to offset the weight inducing properties of high fat (high energy) diets.     

Relationships between changes in body composition and changes in cardiovascular risk factors: the SOS Intervention Study. Swedish Obese Subjects

Relationships between 2-year changes in body composition (estimated from computed tomography-validated anthropometry based on sagittal trunk diameter, weight, and height), adipose tissue (AT) distribution, and cardiovascular risk factors (blood pressure, lipids, glucose, insulin, uric acid) were examined in 842 treated adults with severe obesity with weight changes from -95.5 to +30.6 kg. Although the change (delta) of visceral AT mass (expressed in % total AT) for a given change in body mass index (delta BMI) was 6-fold larger in men than in women, delta waist and delta waist/hip were similar in both sexes. In men, risk factor changes were similarly related to delta waist, delta bodyweight, and delta BMI, whereas in women, delta bodyweight seemed to be the single independent variable with the highest explanatory power. In multivariate regressions adjusted for delta BMI and baseline conditions, delta visceral AT mass was more strongly associated with risk factor changes than were delta waist and delta waist/hip. When using a three-compartment model (lean body mass, subcutaneous and visceral AT masses) plus neck and thigh girths (indicators of subcutaneous AT distribution), risk factor changes were related both to delta subcutaneous and delta visceral AT masses but not to delta lean body mass. In agreement with cross-sectional findings, delta neck was positively and delta thigh was negatively related to some risk factor changes. Thus, the use of waist as a single risk factor indicator seems less effective for epidemiological studies than the simple anthropometric measures presented here, which are able to separate the effects of visceral AT mass, subcutaneous AT mass, and subcutaneous AT distribution on metabolic parameters under both cross-sectional and longitudinal conditions.     

Serum immunoreactive leptin concentration and its relation to the body fat content in chronic renal failure

Leptin, secreted from fat cells, functions as a lipostat mechanism through modulation of satiety signals. The role of leptin in humans has been only partly revealed. However, obese patients have markedly elevated levels of this hormone, and in both normal-weight and obese subjects there is a direct correlation between serum leptin levels and the percentage of body fat. The aim of the present study was to investigate the role of leptin and its relation to body fat content in chronic renal failure (CRF), a disorder associated with decreased appetite. Serum leptin levels and body composition (dual-energy x-ray absorptiometry) were measured in a cohort of 59 patients with terminal CRF (creatinine clearance rate, 8 +/- 1 ml/min). Sixteen of the patients were re-evaluated after 12 mo of peritoneal dialysis treatment, and eight patients were re-evaluated after 12 mo of hemodialysis treatment. The mean serum leptin concentrations were markedly higher (mean +/- SEM) in patients with CRF than in healthy control subjects matched for gender and body mass index (25.7 +/- 5.2 ng/ml versus 8.4 +/- 0.9 ng/ml; P < 0.001). Patients with ongoing signs of inflammation (C-reactive protein > 10 mg/L) demonstrated higher serum leptin levels (41.9 +/- 13.7 ng/ml versus 18.6 +/- 4.2 ng/ml; P < 0.05) than patients with normal C-reactive protein. A strong positive correlation (rho = 0.83; P < 0.0001) was found between serum leptin concentrations and the percentage of body fat. After 12 mo of peritoneal dialysis, the amount of body fat increased markedly (19.0 +/- 1.5 to 25.1 +/- 2.2 kg; P < 0.001), and the changes in serum leptin concentrations correlated significantly (rho = 0.69; P < 0.01) to the changes in the body fat content. In contrast, no significant changes in either body fat content or serum leptin levels were recorded in the eight patients that were re-evaluated after 12 mo of hemodialysis. Serum leptin concentrations are approximately three times higher in patients with CRF compared with healthy control subjects with a similar body mass index. In this study, it is also demonstrated that serum leptin is a good marker for the body fat content in CRF patients and correlates strongly to changes in body fat during 12 mo of peritoneal dialysis. These findings suggest that serum leptin could serve as a valuable clinical marker for the body fat content in patients with CRF. Further studies are needed to verify the hypothesis that increased serum leptin concentrations may contribute to uremic anorexia.     

Impact of hydration status on body composition as measured by dual energy X-ray absorptiometry in normal volunteers and patients on haemodialysis

To evaluate the influence of hydration status on the estimation of body composition using dual-energy X-ray absorptiometry (DXA), six normal volunteers and seven patients on maintenance haemodialysis were investigated using two different DXA machines (Lunar DPX, Hologic QDR 1000/W). Normal volunteers were studied (Hologic QDR 1000/W) before and 1 h after ingestion of breakfast, lunch and dinner (drinking various amounts of liquids at each meal, 0.5-2.4 kg). Whereas bone mineral content and body fat mass did not change, lean body mass of the trunk increased as a consequence of the meals. Conversely in patients on haemodialysis (Lunar DPX), lean body mass decreased in all segments of the body as a consequence of removal of 0.9-4.4 kg of salt-containing fluid by haemodialysis (trunk 61%, legs 30%, arms 5.5% and rest of the body 3.5%), whereas bone mineral content and body fat mass remained unchanged. However, this finding(s) did not hold true in one particular patient with bilateral hip prostheses. Measurement of body composition in eight normal volunteers on the same day with both machines showed similar results for lean and fat mass, whereas bone mineral content was found to be 17% higher using the Lunar DPX. In summary, in centres where both machines are available, follow-up of one individual patient should always be performed using the same equipment. In addition, hydration status and food intake must be taken into account when repetitive measurements of lean body mass are performed in the same patient.     

Serum leptin levels in women with anorexia nervosa

Leptin is a protein encoded by the ob gene that is expressed in adipocytes and regulates eating behavior via central neuroendocrine mechanisms. Serum leptin levels have been shown to correlate with weight and percent body fat in normal and obese individuals; however, it is not known whether the regulation of leptin is normal below a critical threshold of body fat in chronic undernutrition. We investigated serum leptin levels in 22 women, aged 23 +/- 4 yr, with anorexia nervosa. Duration of disease, weight, BMI, percent body fat, and serum leptin levels were determined for each patient. Nutritional status was assessed further by caloric intake and measurement of insulin and insulin-like growth factor I (IGF-I) levels. Twenty-three healthy women, aged 23 +/- 4 yr, taking no medications, with normal menstrual function and body mass index (BMI) between 20-26 kg/m2 (mean, 23.7 +/- 1.7 kg/m2), served as a control population for comparison of leptin levels. Subjects with anorexia nervosa were low weight (BMI, 16.3 +/- 1.6 kg/m2; normal, 20-26 kg/m2) and exhibited a striking reduction in percent body fat (7 +/- 2%; normal, 20-30%). The mean serum leptin level was significantly decreased in subjects with anorexia nervosa compared with that in age- and sex-matched controls of normal body weight (5.6 +/- 3.7 vs. 19.1 +/- 8.1 ng/mL; P < 0.0001). Serum leptin levels were correlated highly with weight, as expressed either BMI (r = 0.66; P = 0.002) or percent ideal body weight (r = 0.68; P = 0.0005), body fat (r = 0.70; P = 0.0003), and IGF-I (r = 0.64; P = 0.001), but not with caloric intake or serum levels of estradiol or insulin in subjects with anorexia nervosa. The correlation between leptin and body fat was linear, with progressively lower, but detectable, leptin levels measured even in patients with less than 5% body fat, but was not significant when the effects of weight were taken into account. In contrast, the correlation between leptin and IGF-I remained significant when the effects of weight, body fat, and caloric intake were taken into account. In normal controls, leptin correlated with BMI (r = 0.55; P = 0.007) and IGF-I (r = 0.44; P < 0.05), but not with fat mass. These data demonstrate that serum leptin levels are reduced in association with low weight and percent body fat in subjects with anorexia nervosa compared to normal controls. Leptin levels correlate highly with weight, percent body fat, and IGF-I in subjects with anorexia nervosa, suggesting that the physiological regulation of leptin is maintained in relation to nutritional status even at an extreme of low weight and body fat.     

Reconstruction of lateral skull base oncological defects: the role of free tissue transfer

The present study was performed to investigate the age-dependent changes in body composition and the possible role of growth hormone (GH), insulin-like growth factor (IGF)-I and IGF-binding protein-3 (IGFBP-3) in these changes in postmenopausal Japanese women. A total of 161 Japanese women aged 45-88 years (mean 62) were enrolled in the cross-sectional study. Body composition (bone mineral content (BMC), lean body mass (LBM) and fat) was measured by dual-energy X-ray absorptiometry, and the percentage of BMC, LBM and fat was calculated by dividing each absolute value of body composition by total body mass. Urinary GH concentration divided by creatinine in nocturnal urine samples collected just after waking was used as an index of endogenous GH secretion. Serum levels of IGF-I and IGFBP-3 were measured by RIA. Urinary GH levels as well as serum levels of IGF-I and IGFBP-3 declined with age. BMC, %BMC and LBM also declined with age, while fat mass and %fat did not obviously change with age. Urinary GH levels as well as serum levels of IGF-I and IGFBP-3 correlated positively with BMC, even if age was taken into account. On the other hand, urinary GH correlated negatively with fat and %fat. In contrast, serum levels of IGF-I and IGFBP-3 correlated positively with fat and %fat. LBM did not correlate with either urinary GH or serum IGFBP-3 levels but exhibited a weakly positive correlation with serum IGF-I level. The present study suggests that the GH-IGF-I-IGFBP-3 axis positively regulates bone mass, and that GH and IGF-I-IGFBP-3 inversely regulate fat mass, i.e. GH negatively and IGF-I-IGFBP-3 positively regulates it.     

Differential impact of conventional oral or transdermal hormone replacement therapy or tibolone on body composition in postmenopausal women

OBJECTIVE: To compare the effects on body composition and body weight of tibolone vs two different sequential oral or transdermal oestrogen-progestogen hormone replacement therapies versus no therapy. PATIENTS AND METHODS: One hundred postmenopausal women were assigned to a control group (n = 26), or randomized to 1) tibolone (TIB) 2.5 mg/day (n = 28), 2) oral oestradiol 2 mg/day (PO) plus sequential dydrogesterone 10 mg/day for 14 of 28 days per cycle (n = 26), or 3) transdermal oestradiol patch (TTS) releasing 50 micrograms/day plus oral sequential dydrogesterone 10 mg/day for 14 of 28 days per cycle (n = 20). Body composition was measured at the base-line and every 6 months for 2 years by DXA (Hologic QDR 1000 W). RESULTS: Total body fat mass increased (P < 0.05) in controls (+3.6 +/- 1.5%) and in TTS treated (+4.7 +/- 2.2%), but not in PO (-1.2 +/- 2.4%) and TIB (-1.6 +/- 2.2%) treated subjects. This increase in total fat mass in controls and TTS treated women was mostly due to an increase in fat mass of the trunk (P < 0.05), but not legs. As a result, a redistribution of body fat to the trunk occurred in controls, TTS and TIB, but not in PO treated women (P < 0.05). Total lean body mass decreased (P < 0.02) in controls (-1.7 +/- 0.7%) and PO (-1.4 +/- 0.6%) but not in TTS (+0.3 +/- 0.8%) and TIB (+0.4 +/- 0.5%) treated subjects. CONCLUSIONS: The menopause is associated with an increase in total body fat and a decline in lean body mass. Oral oestradiol/dydrogesterone and tibolone prevent total body fat changes, whereas transdermal oestradiol/oral dydrogesterone and tibolone prevent the lean mass changes. Furthermore, oral oestradiol/dydrogesterone prevents the shift to a central, android fat distribution.     

Adeno-associated virus vector containing the herpes simplex virus thymidine kinase gene causes complete regression of intracerebrally implanted human gliomas in mice, in conjunction with ganciclovir administration

Weight gain is a major side-effect of treatment with clozapine. In order to investigate the influence of the atypical neuroleptic clozapine on leptin secretion, serum leptin levels were measured in 12 patients at baseline and for a 10-week period after initiation of treatment. Serum clozapine levels and levels of its metabolites were simultaneously assessed. Alterations of body weight and body composition were determined. During the 10-week observation period leptin levels differed significantly from the levels determined at baseline (P < 0.0001). During the first 2 weeks of treatment serum leptin levels at least doubled in eight of the 12 patients. The maximal relative increase over baseline was 536%. Low doses of clozapine were sufficient to induce this effect. Within a 10-week period mean body weight, mean body mass index, mean fat mass and mean lean body mass all increased. Based on the results we suggest that in predisposed individuals clozapine induces an increased appetite; overeating and weight gain can ensue, which in turn underlie elevated leptin secretion.